Comparative activity of various compounds against clinical strains of herpes simplex virus

The following compounds were evaluated for their inhibitory activity against clinical strains of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in both primary rabbit kidney (PRK) and HeLa cell cultures: (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (HPMPA), 9-(2-phosphonylmethoxyethyl)adenine (PMEA), (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC), (RS)-9-(3-hydroxy-2-phosphonylmethoxypropyl)-2,6-diaminopurine (HPMPDAP), 5-(5-bromothien-2-yl)-2-deoxyuridine (BTDU), 5-(5-chlorothien-2-yl)-2-deoxyuridine (CTDU), 9-(2-deoxy-2-hydroxymethyl--D-erythro-oxetanosyl)guanine (OXT-G), pentosan polysulfate, heparin, dextran sulfate (MW 10,000), acyclovir, 9-(2-hydroxyethoxymethyl)guanine (ACV), (E)-5-(2-bromovinyl)-2-deoxyuridine (BVDU), 1--D-arabinofuranosyl-(E)-5-(2-bromovinyl)-uracil (BVaraU), vidarabine (9--D-arabinofuranosyladenine) (ara-A) and phosphonoformate (PFA). The most potent inhibitors of HSV-1 were (in order of decreasing activity in PRK cells) BVDU, ACV, BVaraU and OXT-G, their mean 50 % inhibitory concentration (IC₅₀) ranging from 0.02 µg/ml to 0.9 µg/ml. Then followed BTDU and CTDU (IC₅₀ 1–2 µg/ml), the sulfated polysaccharides (IC₅₀ 1.3–5.8 µg/ml), the phosphonylmethoxyalkyl derivatives (IC₅₀ 5.6–25 µg/ml), ara-A (IC₅₀ 11 µg/ml) and PFA (IC₅₀ 38.5 µg/ml). Except for BVDU, BVaraU, BTDU and CTDU, the compounds did not discriminate between HSV-2 and HSV-1. All the compounds studied could be considered specific anti-HSV agents. Their selectivity indexes varied from 3 (PFA) to 6400 (BVDU).     

Patterns of resistance and sensitivity to antiviral compounds of drug-resistant strains of human cytomegalovirus selected in vitro

Drug-resistant human Cytomegalovirus (HCMV) strains were selected in human embryonic lung (HEL) fibroblasts under pressure of the (S)-3-hydroxy-2-phosphonylmethoxypropyl (HPMP) derivatives of cytosine (HPMPC) and adenine (HPMPA), the 2-phosphonylmethoxyethyl (PME) derivative of 2,6-diaminopurine (PMEDAP), ganciclovir (GCV), acyclovir (ACV), and foscarnet (PFA). Drug susceptibility profiles of the different drug-resistant (i.e., GCV^r, HPMPC^r, HPMPA^r, PFA^r, ACV^r, and PMEDAP^r) strains were determined in HEL cells. A considerable degree of cross-resistance against GCV, HPMPC, and HPMPA occurred with the GCV^r, HPMPC^r, and HPMPA^r strains. No changes in susceptibility to 9-(2-phosphonylmethoxyethyl)adenine (PMEA), PMEDAP, ACV, or PFA were detected for the HPMPC^r, HPMPA^r, and GCV^r strains when compared to the wild-type virus. On the other hand, a significant degree of cross-resistance was noted with the PMEDAP^r, PFA^r, and ACV^r strains against PMEA, PMEDAP, PFA, and ACV. No differences in susceptibility to HPMPC, HPMPA and GCV were observed for the ACV^r, PFA^r, and PMEDAP^r strains relative to the wild type. The drug susceptibility profiles of the different resistant strains point to a common mechanism of HCMV resistance to PFA and the PME derivatives that is different from the mechanism of HCMV resistance to the HPMP derivatives.     

Induction of a refractory state to viral infection in mammalian cells by a plant inhibitor isolated from leaves of Melia azedarach L

A partially purified plant inhibitor (Meliacin) isolated from Melia azedarach L induced in cells a refractory state to virus infection. Meliacin was active in a large variety of continuous and/or primary cell cultures. A state of maximum virus resistance was achieved after 2 h of incubation and was maintained for at least 15 h; later on it declined but it was fully regained after a second pulse of Meliacin. Interferon was not detected in the supernatant of cells treated with Meliacin and a measurable increase in ds-RNA dependent protein kinase activity was not observed in extracts of Meliacin-treated cells. The antiviral state was not transferred by either extracellular fluid or direct cell-to-cell contact. An active cell metabolism was required for Meliacin action, which was partially reversed in the presence of actinomycin D. It appears that Meliacin is not an interferon-like substance, which induces an antiviral state based on a still unexplained mechanism.     

Imaging the effective networks associated with cortical function through intracranial high‐frequency stimulation

Direct electrical stimulation (DES) is considered to be the gold standard for mapping cortical function. A careful mapping of the eloquent cortex is key to successful resective or ablative surgeries, with a minimal postoperative deficit, for treatment of drug‐resistant epilepsy. There is accumulating evidence suggesting that not only local, but also remote activations play an equally important role in evoking clinical effects. By introducing a new intracranial stimulation paradigm and signal analysis methodology allowing to disambiguate EEG responses from stimulation artifacts we highlight the spatial extent of the networks associated with clinical effects. Our study includes 26 patients that underwent stereoelectroencephalographic investigations for drug‐resistant epilepsy, having 337 depth electrodes with 4,351 contacts sampling most brain structures. The routine high‐frequency electrical stimulation protocol for eloquent cortex mapping was altered in a subtle way, by alternating the polarity of the biphasic pulses in a train, causing the splitting the spectral lines of the artifactual components, exposing the underlying tissue response. By performing a frequency‐domain analysis of the EEG responses during DES we were able to capture remote activations and highlight the effect''s network. By using standard intersubject averaging and a fine granularity HCP‐MMP parcellation, we were able to create local and distant connectivity maps for 614 stimulations evoking specific clinical effects. The clinical value of such maps is not only for a better understanding of the extent of the effects'' networks guiding the invasive exploration, but also for understanding the spatial patterns of seizure propagation given the timeline of the seizure semiology.     

External biliary fistulas selectively managed by endoscopic retrograde cholangiography with sphincterotomy and/or stent placement

External bile duct fistulas are inherent postoperative complications that usually appear after biliary tract surgery, traumatic bile duct injuries and liver surgery for hepatic hydatid disease or liver transplant. The management is highly individualized, while the success and long-term results of endoscopic and surgical techniques are conflicting. The study included 32 cases with external bile duct fistulas managed by endoscopic retrograde cholangiography (ERC) with sphincterotomy and/or stent placement, including "rendez-vous" procedures in 2 cases. The causes of the external fistula were represented by cholecystectomy with/without retained common bile duct stones or strictures (22 cases), cholecystectomy and drainage of a subphrenic abscess caused by severe acute pancreatitis (1 case) and surgical interventions for hepatic hydatid disease (9 cases). Due to the prospective protocol of the study we were able to apply an individualized endoscopic treatment: sphincterotomy with proper relief of the bile duct obstruction (stone extraction) or sphincterotomy with large-size (10 Fr) stent placement for large-sized bile duct defects. The results consisted in closure of the fistula in 3.5 +/- 1.7 days for the subgroup of patients with sphincterotomy alone. Among the patients with stent insertion, fistulas healed slower in 14 +/- 3.5 days. There were no complications after endoscopic treatment; however the stent could not be passed in one patient that required subsequent surgery. In conclusion, endoscopic intervention is the treatment of choice for small external biliary fistulas complicating biliary tract surgery or liver surgery for hepatic hydatid disease. When the fistula is large, the placement of a 10 Fr endoprosthesis becomes necessary, while failure of endoscopic treatment leads to surgery with hepatico-jejunal anastomosis.     

Correlation between sagittal plane changes and adjacent segment degeneration following lumbar spine fusion

Adjacent segment degeneration following lumbar spine fusion remains a widely acknowledged problem, but there is insufficient knowledge regarding the factors that contribute to its occurrence. The aim of this study is to analyse the relationship between abnormal sagittal plane configuration of the lumbar spine and the development of adjacent segment degeneration. Eighty-three consecutive patients who underwent lumbar fusion for degenerative disc disease were reviewed retrospectively. Patients with spondylolytic spondylolisthesis and degenerative scoliosis were not included in this study. Mean follow-up period was 5 years. Results were analysed to determine the association between abnormal sagittal configuration and post operative adjacent segment degeneration. Thirty-one out of 83 patients (36.1%) showed radiographic evidence of adjacent segment degeneration. Patients with normal C7 plumb line and normal sacral inclination in the immediate post operative radiographs had the lowest incidence of adjacent level change compared with patients who had abnormality in one or both of these parameters. The difference was statistically significant (P<0.02). There was no statistically significant difference in the incidence of adjacent level degeneration between male and female patients; between posterior fusion alone and combined posterolateral and posterior interbody fusions; and between fusions extending down to the sacrum and fusions stopping short of the sacrum. It was concluded was that normality of sacral inclination is an important parameter for minimizing the incidence of adjacent level degeneration. Retrolisthesis was the most common type of adjacent segment change. Patients with post operative sagittal plane abnormalities should preferably be followed-up for at least 5 years to detect adjacent level changes.     

Liraglutide protects Rin‐m5f β cells by reducing procoagulant tissue factor activity and apoptosis prompted by microparticles under conditions mimicking Instant Blood‐Mediated Inflammatory Reaction

Instant Blood‐Mediated Inflammatory Reaction (IBMIR) occurs at the vicinity of transplanted islets immediately after intraportal infusion and is characterized by cytokine secretion, tissue factor (TF) expression, and ß cell loss. Microparticles (MPs) are cellular effectors shed from the plasma membrane of apoptotic cells. Modulation of the properties of ß cell‐derived MPs by liraglutide was assessed in a cellular model designed to mimic IBMIR oxidative and inflammatory conditions. Rin‐m5f rat β cells were stimulated by H₂O₂ or a combination of IL‐1β and TNF‐α. Cell‐derived MPs were applied to naive Rin‐m5f for 24 h. Apoptosis, MP release, TF activity, P‐IκB expression, and MP‐mediated apoptosis were measured in target cells. Direct protection by liraglutide was shown by a significant decrease in the oxidative stress‐induced apoptosis (18.7% vs. 7.6%, P < 0.0001 at 1 μm liraglutide) and cellular TF activity (?40% at 100 nm liraglutide). Indirect cytoprotection led to 20% reduction in MP generation, thereby lowering MP‐mediated apoptosis (6.3% vs. 3.7%, P = 0.022) and NF‐κB activation (?50%) in target cells. New cytoprotective effects of liraglutide were evidenced, limiting the expression of TF activity by ß cells and the generation of noxious MPs. Altogether, these data suggest that liraglutide could target pro‐apoptotic and pro‐inflammatory MPs in transplanted islets.     

Computer-assisted cystoscopy diagnosis of bladder cancer

Objectives

One of the most reliable methods for diagnosing bladder cancer is cystoscopy. Depending on the findings, this may be followed by a referral to a more experienced urologist or a biopsy and histological analysis of suspicious lesion. In this work, we explore whether computer-assisted triage of cystoscopy findings can identify low-risk lesions and reduce the number of referrals or biopsies, associated complications, and costs, although reducing subjectivity of the procedure and indicating when the risk of a lesion being malignant is minimal.

Changes in the incidence and management of spinal tuberculosis in a French University Hospital Rheumatology Department from 1966 to 2010

IntroductionTwo previous single-center studies in a university hospital rheumatology department suggested an increase in the incidence of spinal tuberculosis in France in the 1990s. Our objective in this study was to obtain incidence data on spinal tuberculosis since 1995 in the same department and to describe changes over the entire study period from 1966 to 2010. We also compared patients seen between 1966 and 1995 to those seen between 1995 and 2010.MethodsWe conducted a retrospective review of all cases of spinal tuberculosis seen in our rheumatology department between 1966 and June 1995 and between July 1995 and 2010. We collected the annual incidence, clinical and radiological features, and diagnostic and therapeutic strategies.ResultsOne hundred and thirty patients were managed between 1966 and 2010. The number of cases declined in the 1970s and 1980s then increased over the next two decades. None of the patients had HIV infection. Over 70% of patients were from continental France. Compared to patients seen during the earlier period, those seen after June 1995 were older (62.8 ± 17.2 vs. 53 ± 14.3 years, P = 0.0006), had more comorbidities, and more often exhibited severe radiological findings (including multilevel involvement, epidural involvement, and abscesses). No changes occurred in time to diagnosis or management strategies.ConclusionThe incidence of spinal tuberculosis in a university hospital rheumatology department has increased over the last two decades, chiefly as a result of reactivation of past tuberculosis, as opposed to origin from endemic countries or HIV infection.